Inflammation can be effectively controlled by inhibiting the formation of inflammatory mediators like eicosanoids such as prostaglandins, thromboxanes, and leukotrienes. The formation of such eicosanoids, by oxidation of arachidonic acid released from cell membranes, is mediated by cyclooxygenase (COX) and lipoxygenase (LOX) enzymes. The search for inhibitors of COX and LOX enzymes, to suppress formation of inflammatory mediators, is the basis for developing certain new anti-inflammatory agents. However, recent studies revealed that COX inhibitors causes side effects, especially those leading to cardiovascular problems. The alternative pathway mediated by 5-lipoxygenase has thus become an important target for the development of anti-inflammatory drugs.
5-Lipoxygenase is an important enzyme in the biosynthesis of leukotriene. 5-Lipoxygenase inhibitors bind to the 5-Lipoxygenase enzyme, interrupting leukotriene formation. Leukotriene is the main mediator for a variety of inflammation and hypersensitivity related human diseases, including, but not limited to, arthritis, asthma, and bowel-complication syndromes such as ulcerative colitis and Crohn's disease. Leukotriene also is responsible for certain circulatory disorders, for example, shock and myocardial ischemia.
In this respect, many efforts have been undertaken to isolate natural lipoxygenase inhibitors. For example, some have focused on pentacyclic triterpenoidal frameworks for 5-lipoxygenase inhibitors. Others have focused efforts on chemical alterations of these molecules, attempting to increase their activity as a 5-lipoxygenase inhibitor. 11-keto-β-boswellic acid—a pentacyclic triterpene molecule plant product—has been found to inhibit 5-lipoxygenase via an enzyme-directed, non-competitive mechanism, binding to a pentacyclic triterpene-selective effector site.
Thus, it would be desirable to synthesize and identify additional potent pentacyclic triterpenoidal derivatives for inhibiting 5-lipoxygenase. Such derivatives may prove useful in treating various diseases and adverse health conditions.